| 1. |
- Abdelmagid, Nada Omar
(författare)
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Genetic regulation of neuroinflammation after infection and injury
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroinflammation is a common theme in a spectrum of central nervous system (CNS) diseases resulting in neuronal damage and degeneration. The exact mechanisms regulating inflammation in the CNS or its consequences in terms of nerve injury are still not known in detail. However, it is known that many inflammatory conditions at least in part are regulated by genetic factors. Exact definition of these factors will provide a better understanding of underlying mechanisms. The focus of this thesis has been to explore the genetic regulation of neuroinflammation in viral infections and mechanical nerve injuries using experimental models. The genetic regulation of susceptibility to Herpes simplex type-1 encephalitis (HSE), a devastating condition that affects humans, was investigated in different inbred rat strains. Using a series of different experimental approaches we succeeded in defining two different candidate genes that regulate susceptibility to HSE. Interestingly, these genetic influences act at two different stages of neurotropic HSV-1 virus CNS entry. Thus, the calcitonin receptor (Calcr) gene was identified as a candidate for peripheral neuronal infection and propagation to the CNS, while the von Willebrand factor (Vwf) gene was identified as a candidate for disease progression in the CNS and blood-brain barrier (BBB) dysfunction. The latter has previously been associated to cerebral malaria infection by Plasmodium falciparum and endothelial cell activation, suggesting that this gene is important in several human infectious conditions. More detailed histopathological and molecular studies of HSV-1 propagation, immune cell recruitment and inflammatory changes was the focus of another study, which provides further support for the notion that entry of virus into the perineurium is an important step regulating susceptibility for virus propagation into the CNS. Also, the differences found between the studied strains in relation to immune activation and responses in the peripheral nervous system (PNS) and CNS clearly demonstrate that genetic factors regulate virus - host interactions. Thus, our studies on HSE have provided several new perspectives of how susceptibility to HSV-1 virus can be regulated at different levels, as well as identifying two different candidate genes, all of which can serve as basis for further studies of human HSE. In a fourth study, the genetic regulation of the response to a mechanical nerve injury was explored in order to identify regulatory pathways for innate immune responses occurring without an infectious trigger. We identified two quantitative trait loci (QTLs) on chromosome 1 (Neuinflam4) and 7 (Neuinflam5), respectively, regulating major histocompatibility complex class II (MHC II) expression after ventral root avulsion. Additionally, another QTL (Neuinflam9) on chromosome 10 regulated the expression of several important innate immune genes, including C1q, Il1β, Tlr2 and Irf7. The chromosome 10 region containing Neuinflam9 overlaps with Toxo1, which regulates resistance to Toxoplasma gondii infection. Interestingly, a part of this QTL conferred resistance to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS) indicating that this QTL could regulate susceptibility both to infectious and autoimmune conditions. In conclusion, the identification of several genetically regulated pathways presented herein provides a basis for further molecular exploration of different conditions characterized by neuroinflammation. This will be a necessary prerequisite for the formulation of new targeted therapeutic interventions that can prevent permanent damage to the nervous system.
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| 2. |
- Abdelmagid, Nada, et al.
(författare)
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The Governance of Childhood Vaccination Services in Crisis Settings : A Scoping Review
- 2023
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Ingår i: Vaccines. - : MDPI. - 2076-393X. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- The persistence of inadequate vaccination in crisis-affected settings raises concerns about decision making regarding vaccine selection, timing, location, and recipients. This review aims to describe the key features of childhood vaccination intervention design and planning in crisis-affected settings and investigate how the governance of childhood vaccination is defined, understood, and practised. We performed a scoping review of 193 peer-reviewed articles and grey literature on vaccination governance and service design and planning. We focused on 41 crises between 2010 and 2021. Following screening and data extraction, our analysis involved descriptive statistics and applying the governance analysis framework to code text excerpts, employing deductive and inductive approaches. Most documents related to active outbreaks in conflict-affected settings and to the mass delivery of polio, cholera, and measles vaccines. Information on vaccination modalities, target populations, vaccine sources, and funding was limited. We found various interpretations of governance, often implying hierarchical authority and regulation. Analysis of governance arrangements suggests a multi-actor yet fragmented governance structure, with inequitable actor participation, ineffective actor collaboration, and a lack of a shared strategic vision due to competing priorities and accountabilities. Better documentation of vaccination efforts during emergencies, including vaccination decision making, governance, and planning, is needed. We recommend empirical research within decision-making spaces.
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| 3. |
- Allison, Lauren E, et al.
(författare)
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A Systematic Review of Vaccination Guidance for Humanitarian Responses
- 2023
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Ingår i: Vaccines. - : MDPI. - 2076-393X. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- Delivering vaccines in humanitarian response requires rigourous and continuous analysis of evidence. This systematic review mapped the normative landscape of vaccination guidance on vaccine-preventable diseases in crisis-affected settings. Guidance published between 2000 and 2022 was searched for, in English and French, on websites of humanitarian actors, Google, and Bing. Peer-reviewed database searches were performed in Global Health and Embase. Reference lists of all included documents were screened. We disseminated an online survey to professionals working in vaccination delivery in humanitarian contexts. There was a total of 48 eligible guidance documents, including technical guidance (n = 17), descriptive guidance (n = 16), operational guidance (n = 11), evidence reviews (n = 3), and ethical guidance (n = 1). Most were World Health Organization documents (n = 21) targeting children under 5 years of age. Critical appraisal revealed insufficient inclusion of affected populations and limited rigour in guideline development. We found limited information on vaccines including, yellow fever, cholera, meningococcal, hepatitis A, and varicella, as well as human papilloma virus (HPV). There is a plethora of vaccination guidance for vaccine-preventable diseases in humanitarian contexts. However, gaps remain in the critical and systematic inclusion of evidence, inclusion of the concept of "zero-dose" children and affected populations, ethical guidance, and specific recommendations for HPV and non-universally recommended vaccines, which must be addressed.
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| 4. |
- Ayoglu, Burcu, et al.
(författare)
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Anoctamin 2 identified as an autoimmune target in multiple sclerosis
- 2016
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences of the USA. - 0027-8424 .- 1091-6490. ; 113:8, s. 2188-2193
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.
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| 5. |
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| 6. |
- Bile, Ahmed Said, et al.
(författare)
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Assessing Vaccination Delivery Strategies for Zero-Dose and Under-Immunized Children in the Fragile Context of Somalia
- 2024
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Ingår i: Vaccines. - : MDPI. - 2076-393X. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- Somalia is one of 20 countries in the world with the highest numbers of zero-dose children. This study aims to identify who and where zero-dose and under-vaccinated children are and what the existing vaccine delivery strategies to reach zero-dose children in Somalia are. This qualitative study was conducted in three geographically diverse regions of Somalia (rural/remote, nomadic/pastoralists, IDPs, and urban poor population), with government officials and NGO staff (n = 17), and with vaccinators and community members (n = 52). The data were analyzed using the GAVI Vaccine Alliance IRMMA framework. Nomadic populations, internally displaced persons, and populations living in remote and Al-shabaab-controlled areas are three vulnerable and neglected populations with a high proportion of zero-dose children. Despite the contextual heterogeneity of these population groups, the lack of targeted, population-specific strategies and meaningful engagement of local communities in the planning and implementation of immunization services is problematic in effectively reaching zero-dose children. This is, to our knowledge, the first study that examines vaccination strategies for zero-dose and under-vaccinated populations in the fragile context of Somalia. Evidence on populations at risk of vaccine-preventable diseases and barriers to vital vaccination services remain critical and urgent, especially in a country like Somalia with complex health system challenges.
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| 7. |
- Diez, Margarita, et al.
(författare)
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Identification of gene regions regulating inflammatory microglial response in the rat CNS after nerve injury
- 2009
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 212:1-2, s. 82-92
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Tidskriftsartikel (refereegranskat)abstract
- Local CNS inflammation takes place in many neurological disorders and is important for autoimmune neuroinflammation. Microglial activation is strain-dependent in rats and differential MHC class II expression is influenced by variations in the Mhc2ta gene. Despite sharing Mhc2ta and MHC class II alleles, BN and LEW.1N rats differ in MHC class II expression after ventral root avulsion (VRA). We studied MHC class II expression and glial activation markers in BN rats after VRA. Our results demonstrate that MHC class II expression originates from a subpopulation of IBA1(+), ED1(-), and ED2(-) microglia. We subsequently performed a genome-wide linkage scan in an F2(BNxLEW.1N) population, to investigate gene regions regulating this inflammatory response. Alongside MHC class II, we studied the expression of MHC class 1, costimulatory molecules, complement components, microglial markers and Il1b. MHC class II and other transcripts were commonly regulated by gene regions on chromosomes 1 and 7. Furthermore, a common region on chromosome 10 regulated expression of complement and co-stimulatory molecules, while a region on chromosome II regulated MHC class I. We also detected epistatic interactions in the regulation of the inflammatory process. These results reveal the complex regulation of CNS inflammation by several gene regions, which may have relevance for disease. (C) 2009 Elsevier B.V. All rights reserved.
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| 8. |
- Lindahl, Hannes, et al.
(författare)
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IL-22 Binding Protein Promotes the Disease Process in Multiple Sclerosis
- 2019
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Ingår i: Journal of Immunology. - : AMER ASSOC IMMUNOLOGISTS. - 0022-1767 .- 1550-6606. ; 203:4, s. 888-898
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have mapped the specific sequence variants that predispose for multiple sclerosis (MS). The pathogenic mechanisms that underlie these associations could be leveraged to develop safer and more effective MS treatments but are still poorly understood. In this article, we study the genetic risk variant rs17066096 and the candidate gene that encodes IL-22 binding protein (IL-22BP), an antagonist molecule of the cytokine IL-22. We show that monocytes from carriers of the risk genotype of rs17066096 express more IL-22BP in vitro and cerebrospinal fluid levels of IL-22BP correlate with MS lesion load on magnetic resonance imaging. We confirm the pathogenicity of IL-22BP in both rat and mouse models of MS and go on to suggest a pathogenic mechanism involving lack of IL-22-mediated inhibition of T cell-derived IFN-gamma expression. Our results demonstrate a pathogenic role of IL-22BP in three species with a potential mechanism of action involving T cell polarization, suggesting a therapeutic potential of IL-22 in the context of MS.
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| 9. |
- Lindblom, Rickard P. F., et al.
(författare)
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Complement receptor 2 is up regulated in the spinal cord following nerve root injury and modulates the spinal cord response
- 2015
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094 .- 1742-2094. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Activation of the complement system has been implicated in both acute and chronic states of neurodegeneration. However, a detailed understanding of this complex network of interacting components is still lacking. Methods: Large-scale global expression profiling in a rat F2(DAxPVG) intercross identified a strong cis-regulatory influence on the local expression of complement receptor 2 (Cr2) in the spinal cord after ventral root avulsion (VRA). Expression of Cr2 in the spinal cord was studied in a separate cohort of DA and PVG rats at different time-points after VRA, and also following sciatic nerve transection (SNT) in the same strains. Consequently, Cr2(-/-) mice and Wt controls were used to further explore the role of Cr2 in the spinal cord following SNT. The in vivo experiments were complemented by astrocyte and microglia cell cultures. Results: Expression of Cr2 in naive spinal cord was low but strongly up regulated at 5-7 days after both VRA and SNT. Levels of Cr2 expression, as well as astrocyte activation, was higher in PVG rats than DA rats following both VRA and SNT. Subsequent in vitro studies proposed astrocytes as the main source of Cr2 expression. A functional role for Cr2 is suggested by the finding that transgenic mice lacking Cr2 displayed increased loss of synaptic nerve terminals following nerve injury. We also detected increased levels of soluble CR2 (sCR2) in the cerebrospinal fluid of rats following VRA. Conclusions: These results demonstrate that local expression of Cr2 in the central nervous system is part of the axotomy reaction and is suggested to modulate subsequent complement mediated effects.
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| 10. |
- Rosjo, Egil, et al.
(författare)
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Effect of high-dose vitamin D-3 supplementation on antibody responses against Epstein-Barr virus in relapsing-remitting multiple sclerosis
- 2017
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Ingår i: Multiple Sclerosis Journal. - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 23:3, s. 395-402
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Tidskriftsartikel (refereegranskat)abstract
- Background: Elevated antibody levels against Epstein–Barr virus (EBV) and a poor vitamin D status are environmental factors that may interact in relapsing-remitting multiple sclerosis (RRMS) aetiology.Objectives: To examine effects of high-dose oral vitamin D3 supplementation on antibody levels against EBV nuclear antigen 1 (EBNA1) in RRMS.Methods: Serum 25-hydroxyvitamin D3 (25(OH)D) and immunoglobulin G antibody levels against EBNA1 (whole protein and amino acid 385–420 fragment), EBV viral capsid antigen (VCA), cytomegalovirus (CMV) and varicella zoster virus (VZV) were measured in 68 RRMS patients enrolled in a 96-week randomised double-blinded placebo-controlled clinical trial of oral vitamin D3 supplementation (20,000 IU/week) (NCT00785473).Results: The mean 25(OH)D level more than doubled in the vitamin D group and was significantly higher than in the placebo group at study conclusion (123.2 versus 61.8 nmol/L, p < 0.001). Compared to the placebo group, both anti-EBNA1 protein and fragment antibody levels decreased in the vitamin D group from baseline to week 48 (p = 0.038 and p = 0.004, respectively), but not from baseline to week 96. Vitamin D3 supplementation did not affect antibodies against VCA, CMV or VZV.Conclusion: The results indicate that high-dose oral vitamin D3 supplementation can affect humoral immune responses against the latent EBV antigen EBNA1 in RRMS.
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